Atsuomi Baba

Effects of chronic administration of interferon α A/D on serotonergic receptors in rat brain

The effects of chronic administration of interferon (IFN; recombinant human IFN -αA/D) on serotonergic binding sites in rat brain were investigated. IFN was injected daily for 2 weeks at a dose of 100000 I.U./kg, (i.p.) in male Wistar rats. IFN did not alter either [3H]ketanserin binding to 5-HT2A receptors or [3H]paroxetine binding to 5-HT transporters. Scatchard analysis of [3H]8-hydroxy-dipropylaminotetraline (8-OH-DPAT) binding to 5-HT1A receptors demonstrated the presence of high- and low-affinity binding sites in both treatment and control groups. IFN significantly increased both Kd and Bmax measures of [3H]8-OH-DPAT binding at low-affinity binding sites, but not at the high-affinity sites. These results suggest that IFN affects the low-affinity 5-HT1A receptors sites and may be involved in the development of IFN-induced psychiatric disturbances.

High-dose of multiple antipsychotics and cognitive function in schizophrenia: The effect of dose-reduction

We evaluated the effect of antipsychotic dose-reduction on the neurocognitive function of 17 schizophrenic patients (11 male and 6 female, mean age=42.4+/-11.3) who have been taking high-doses of multiple conventional antipsychotics. The mean (+/-SD) of total daily antipsychotic doses (in mg/day, chlorpromazine-equivalent) was 2,253 (+/-668) at baseline, which was reduced to 1,315 (+/-276). Possible changes in neurocognitive function were assessed using Wisconsin card sorting test (WCST) and continuous performance test (CPT). As controls, we examined WCST and CPT in 6 schizophrenic patients (4 male and 2 female, mean age=47.7+/-14.2) who had been taking high-doses of multiple antipsychotics (mean daily antipsychotic dose=1,753+/-165 mg) and declined to change their antipsychotic regimen. In WCST, the mean number of total correct answers significantly increased (53.2+/-16.3 vs. 63.8+/-19.6, P=0.035, Wilcoxon signed rank test); perseverative errors significantly decreased (54.4+/-27.3 vs. 35.4+/-20.1, P=0.013, Wilcoxon signed rank test) after the antipsychotic dose-reduction. In contrast, the control group showed no significant difference between the two WCST performances conducted with a three-month interval. The improvements in WCST performance significantly correlated with the decreases in PANSS negative syndrome score in the subject patients. No significant change was observed in CPT performances in either group. Our preliminary data shows that, in schizophrenic patients taking high-doses of multiple conventional antipsychotics, dose-reduction might lead to improvements in cognitive functions.

Effects of cocaine administration on receptor binding and subunits mRNA of GABAA‐benzodiazepine receptor complexes

The effects of intermittent intraperitoneal (i.p.) administration of cocaine (20 mg/kg) on GABAA‐benzodiazepine (BZD) receptors labeled by t‐[35S]butylbicyclophosphorothionate (TBPS), and on several types of mRNA subunits were investigated in rat brain by in vitro quantitative receptor autoradiography and in situ hybridization. Phosphor screen imaging with high sensitivity and a wide linear range of response was utilized for imaging analysis. There was a significant decrease in the level of α1, α6, β2, β3, and γ2 subunits mRNA, with no alteration of [35S]TBPS binding in any regions in the brain of rats at 1 h following a single injection of cocaine. In chronically treated animals, the mean scores of stereotyped behavior were increased with the number of injections. The level of β3 subunit mRNA was decreased in the cortices and caudate putamen, at 24 h after a final injection of chronic administrations for 14 days. In the withdrawal from cocaine, the frontal cortex and hippocampal complexes showed a significant increase in [35S]TBPS binding and α1 and β3 subunit mRNA in the rats 1 week after a cessation of chronic administration of cocaine. These findings suggest that the disruption of GABAA‐BZD receptor formation is closely involved in the development of cocaine‐related behavioral disturbances. Further studies on the physiological functions on GABAA‐BZD receptor complex will be necessary for an explanation of the precise mechanisms underlying the acute effects, development of hypersensitization, and withdrawal state of cocaine. Synapse 38:198–215, 2000.

An autopsy case of myotonic dystrophy with mental disorders and various neuropathologic features

An autopsy case of myotonic dystrophy (MD) is reported. The patient was a 58‐year‐old male. He presented with muscular weakness and muscular atrophy at the age of 33 and was diagnosed as having MD from myotonic symptoms (i.e. percussion and grip myotonia) at 49 years old. Mental disorders including a delusional hallucinatory state, mental slowness, indifference, and lack of spontaneity as well as visual cognitive impairments were noted at the age of 55. He showed Parkinsonism and died of septic shock. T2‐weighted magnetic resonance imaging demonstrated diffuse cortical atrophy with a marked frontal atrophy and high‐intensity signals in the white matter. Single photon emission computed tomography demonstrated hypoperfusion in the frontal cortex. Neuropathologic observation revealed neuronal loss in the superficial layer of the frontal and parietal cortices and extensive neuronal loss in the occipital cortex, intracytoplasmic inclusion body in the nerve cell of the medial thalamic nuclei, neuronal loss and presence of Lewy bodies in the substantia nigra and locus ceruleus corresponding to the pathologic features of Parkinson’s disease, as well as abnormalities of myelin in the white matter. The present case suggests that in MD brain, various neuropathologic changes may occur and they contribute to the mental disorders.

Effects of single and repeated phencyclidine administration on the expression of metabotropic glutamate receptor subtype mRNAs in rat brain

Recent animal studies regarding phencyclidine (PCP), which induces psychotic symptoms in humans, have suggested that group II metabotropic glutamate receptors (mGluRs) represent a novel target for the treatment of PCP psychosis. In the present study, we used in situ hybridization to investigate the gene expressions of the mGluR 1–5 subtypes following single and repeated administration of PCP in rats. A single administration of PCP (7.5mg/kg, i.p.,) resulted in a significant decrease in the mGluR5 mRNA expression of group I mGluR in the subcortical regions (thalamus (−15%), central gray (−23%), inferior colliculus (−23%), and nucleus accumbens (−10%)) and hippocampal formation (CA1 (−14%), CA2 (−15%), CA3 (−18%), and dentate gyrus (−18%)). After repeated PCP administration for 14 days, the mGluR2 mRNA expression of group II mGluR in the anterior cingulate cortex (−23%) and the mGluR4 mRNA expression of group III mGluR in the cortical regions (parietal (−11%), temporal (-13%) and entorhinal cortices (−18%)), the caudate putamen (−12%), thalamus (−17%), and subiculum (−25%) were significantly decreased. These results indicate that PCP affects not only group II mGluR but also group I and III of mGluR, and it is of particular interest that mGluR2 subtype is involved in a development of behavioral abnormality following repeated PCP administration. Single and repeated administrations of PCP independently regulate the expression of mGluR subtypes of mRNA in the brain.

Differential expression of GABAA receptor subunit mRNAs and ligand binding sites in rat brain following phencyclidine administration

Recent biochemical observations have suggested the abnormalities in the γ‐amino‐butyric acid (GABA)ergic system in schizophrenic brains. In the present study, we investigated the subunits gene expressions and ligand binding of the GABAA receptor following acute and chronic administration of phencyclidine (PCP), which induces schizophrenia‐like symptoms, in rats using in situ hybridization and in vitro quantitative autoradiography. PCP i.p. administration at a daily dose of 7.5 mg/kg resulted in a significant decrease in expression of α1 subunit mRNA in cerebral cortices (cingulate (‐13%) and temporal cortex (‐6%)) and hippocampal formation (CA1 (‐11%), CA2 (‐10%), CA3 (‐11%) and dentate gyrus (‐12%)) 1 h after a single treatment. In the repeated PCP administrations for 14 days, the expression of β2 mRNA in the cerebellum (‐10%) and of β3 mRNA in the cerebral cortices (cingulate (‐12%), parietal (‐16%) and temporal cortex (‐16%), caudate putamen (‐18%), inferior colliculus (‐18%), and cerebellum (‐15%) were significantly decreased. In addition, [35S]t‐butylbicyclophosphorothionate (TBPS) binding was also reduced in layer IV of the frontoparietal cortex (‐14%), inferior colliculus (‐17%), and cerebellum (‐12%) following chronic PCP treatment, while no changes were observed following acute PCP treatment. These results indicate that single and repeated administrations of PCP independently regulate the expression of GABAA/benzodiazepine (BZD) receptor subunits mRNA and its receptor binding in the brain. Synapse 38:51–60, 2000.

Effects of phencyclidine metabolites on serotonin uptake in rat brain

The effects of phencyclidine (PCP) and its metabolites on serotonin (5-hydroxytryptamine, 5-HT) receptors were studied. PCP and its metabolites inhibited the uptake of [3H]5-HT and the binding of [3H]paroxetine in rat brain, while they failed to inhibit either [3H]5-HT binding to 5-HT1 receptors or [3H]ketanserin binding to 5-HT2 receptors. The trans-isomer of 4-phenyl-4-(I-piperidinyl)cyclo-hexanol (trans-4-PPC), the major metabolite of PCP, rather than PCP itself, inhibited [3H]5-HT uptake most potently. These results suggest that the serotonergic effects of PCP, in part, may be based on the effects of PCP metabolites on 5-HT uptake.

Risperidone failed to improve polydipsia-hyponatremia of the schizophrenic patients

Abstract The effect of risperidone on polydipsia‐hyponatremia was evaluated in six hospitalized schizophrenic patients. The normalized diurnal weight gain (NDWG), urine‐specific gravity (USG), urine and plasma osmolarity, and serum sodium were monitored during 9 months of risperidone treatment. The dose of risperidone (mean ± SD = 8.0 ± 1.0, range = 6–9 mg/day) was determined as approximately half of the haloperidol‐equivalent dose of previous neuroleptics. Before risperidone treatment, the mean (± SD) BPRS score was 23.5 ± 7.1; no significant improvement was observed after risperidone (22.0 ± 7.5). The subjects showed relatively high serum prolactin before risperidone treatment (mean ± SD = 16.5 ± 9.7 ng/mL), that was not significantly decreased by risperidone (14.2 ± 7.9 ng/mL). The monthly means (± SD) of NDWG and USG before risperidone were 5.5 ± 1.5 (%) and 1.002 ± 0.001, respectively. These and other indices did not significantly improve throughout the study period. Although the sample size is relatively small, our preliminary data showed that risperidone might not be effective on polydipsia‐hyponatremia of schizophrenic patients.

Autoradiographic localization of CCK-8 binding sites in the rat brain: Effects of chronic methamphetamine administration of these sites

The effects of chronic methamphetamine (MAP) administration (at a dose of 4 mg/kg for 14 days) on [3H]pCCK-8 binding sites in the rat brain were investigated by an in vitro quantitative receptor autoradiographic technique. The number of [3H]pCCK-8 binding sites was significantly reduced in layers III and IV of the medial frontal, anterior, and posterior cingulate cortices, in layers II-IV of the retrosplenial cortex, in layers III-VI of the dorsal insular cortex, and in the reticular nucleus of the thalamus, compared to these numbers in a control group of rats that received physiologic saline. Further, chronic methamphetamine administration led to a significant increase in the number of these binding sites in layer I of the entorhinal cortex. These findings indicate the CCK peptides in the limbic lobe may be closely related to the development of the behavioral changes associated with methamphetamine sensitization. In addition, these results provide supporting evidence for the involvement of the limbic system in the pathophysiology of schizophrenia.

CNS changes in neuro-Behçet's disease : CT, MR, and SPECT findings

CNS changes in three cases of neuro-Behçets disease were observed by computed tomography (CT), magnetic resonance (MR) and single photon emission computed tomography (SPECT). The present study illustrates the reversibility of lesions in the brain stem with MR, while CT failed to show any abnormal findings in the region of the disease. We conclude that MR is a quite useful method to detect lesions in the brain stem and to evaluate the effects of treatment in neuro-Behçets disease. SPECT is also an important method for the evaluation of dementia recognized in neuro-Behçets disease.